21 chloro pregnanes and pregnenes and process



United States Patent 21 CHLORO PREGNANES AND PREGNENES AND PRQCESS Josef Fried and Josef E. Herz, New Brunswick, N. J., 'assignors to Olin Mathieson Chemical Corporation, New York, N. Y., a corporation of Virginia No Drawing. Original application June 4, 1954, Serial No. 434,672, now Patent No. 2,763,671, dated September 18, 1956. Divided and this application September 11, 1957, Serial No. 686,553

5 Claims. (Cl. 260-23955) This application is a division 'of our parent application Serial No. 582,314, filed April 16, 1956, which in turn is a division of application Serial No. 434,672, filed June 4, 1954, and now Patent No. 2,763,671, granted September 18, 1956. a

This invention relates to the synthesis of valuable steroids; and has for its objects the provision of (1) an advantageous process of preparing steroids of 'the pregnane (including the pregnene and allopregnane) series having a 9a-halogen substituent and an l l-keto or 115- hydroxy substituent, and of (II) certain compounds useful themselves as physiologically-active steroids and in the preparation of other physiologically-active steroid derivatives.

The process of this invention essentially comprises (a) converting an 110:,2'l-dihYdI0XY steroid of the pregnane series into the corresponding 11a,21-di(alkanesulfonyloxy) or '11 a-alkane-sulfonyloxy-21-chloro derivatives thereof, b) converting the latter into the corresponding A -21-bromo, chloro, or unsubstituted derivative, (0) converting said 13 compound into the corresponding 9a-bromo or chloro, l'lfl-hydroxy derivative, (d) converting said Qua-bromo or chloro compound'to the corresponding 9,8,llB-oxido,2-l-acetoxy or to the 9,8,llfi-oxido, 21-chloro derivative, and (e) converting said 95,1 oxido derivative to the corresponding 9a-h-alo, lip-hydroxy compound (e. g. 9oc-fillOIOhYdIOCO1iiSOH6 acetate). [The A -2l-bromo derivative formed in step (b) may be converted to the corresponding A ,2l-acetoXy deriv ative.]

The compounds of this invention comprise: (A) 1111, 21-di(alkanesulfonyloxy) and 11u-alkanesulfonyloxyi'h chlorosteroids of the pregnane series; (B) A ,2'1- bromo and chloro steroids of the pregnane series; (C)

u-brorno or chloro, 11,8-hydroXy,21-bromo, steroids of the pregnane series; (D) 9B,'11B-oxido,2l-chloro steroids of the pregnane series; and (E) 9e-halo,l1;3-hydroxy,2'1- chloro steroids of the pregnane series.

For a clearer understanding of the foregoing general and following detailed description of one of the related processes of this invention, reference is made t'o'th'e following schematic analysis:

2,851,455 Patented Sept. ,9, B

ice

wherein the 4,5 position is double-bonded or saturated (the .4,5-double-bonded steroids are preferred), and wherein R is hydrogen, R is hydroxy, or together R and R is oxo (:keto) or a group convertible thereto by hydrolysis (e. g. acetal), 'R and R as oxo being preferred; Z is hydrogen or e-hydroxy; R" is an alkanesulfonyl radical, particularly a lower alkane sulfonyl such as methanesulfonyl, ethanesulfonyl, hexanesulfonyl, etc and is preferably methanesulfonyl; X is chloro, bromo, or iod'oyR is R"O or chloro; Me is a metal, such as an alkali :metal or an alkaline earth metal, the halogen salt of Which is soluble in the solvent employed in the indicated reaction, preferably an alkali metal, such as sodium or lithium; Y is hydrogen, bromo, or chloro; R" X' is an N-bromamide (including imide) of a can boxylic acid (including derivatives), an N-chloramide (including imide) of a carboxylic acid (including derivatives), -dibromodimethylhydantoin, or dichlorodimethylhydantoin; X is bromo or chloro; Y is acetoxy-"or chloro; and X" is a halo fluoro, chloro, bromo, or iodo).

Compounds suitable as initial reactants in the process of this invention set out in the foregoing schematic analysis include compound epi-F (N-pregnene-1'1e,l7u,2-l-trio1-3, 20-dione), epi-corticosterone (A4:pregnene 11u,2-1'-diol-3, 20-dione), 1la,170:,21-trihydroxy-pregnane 3,20 dione, 1'1(1,21-dihydroxypregnane-3,ZO-dione etc. These compounds are reacted with alkanesulfonyl halides (sulfonyl chlorides are preferred but other halides'such as bromides and iodides may be used). Although any alkanesulfonyl chloride may be used, the alkane group .is preferably a lower alkane, methanesulfonyl chloride (mesyl chloride) being particularly preferred. The reaction is carried out in accordance with the general method disclosed in the U. S. application of Josef Fried, Serial No. 4 17,489, filed March 10, 1954, and in the following examples, by'reacting the steroid and sulfonyl halide in the presence of dry pyridine or other tertiary organic base.

This reaction results in the production of compounds A wherein the 'alkanesulfonyloxy radical in the llor position corresponds to the alkanesulfonyl halide used in radical if Z is hydrogen.

Compounds'A are then reacted with a metal halide (MeX) wherein MeX is as above-defined. Particularly preferred metal halides are lithium chloride, lithium bromide and sodium iodide.

Other utilizable salts include beryllium chloride, ca lcium chloride, potassium bromide, calcium bromide, and barium bromide. The reaction is carried out in the presence of at least one mole/mole of steroid of an alkali metal salt of a weak acid, such as an alkali metal lower alkanoate (preferably sodium acetate), an alkali metal carbonate, an alkali metal bicarbonate, etc. The reaction is conducted in a suitable solvent wherein both the metal halide and alkali metal salt of the weak acid are soluble.

Such solvents include the lower alkanoic acids (particularly glacial acetic acid) certain alcohols, and ketones.

This reaction results in the production of compounds B wherein the ZI-substituent is: bromine when a metal bromide is used; chlorine when a metal chloride is used; and hydrogen when a metal iodide is used (the intermediately former 21-iodo derivative having been reduced).

Compounds B are then reacted with RX', wherein R""X' is as above-defined, and is preferably N-bromoacetamide, N-bromosuccinimide, N-chloracetamide, N- chlorosuccinimide, dibromodimethyl hydantoin, or dichlorodimethyl hydantoin, in accordance with the method disclosed in the copending applications of Fried, Serial No. 417,489, filed March 10, 1954, and Fried et al., Serial No. 429,108, filed May 11, 1954. As disclosed in those applications, the conversion is preferably elfected in the presence of perchloric acid or other relatively strong acids. This reaction produces compounds C having a 9a-chloro or bromo substituent and an 11 fi-hydroxy radical.

Compounds C are then reacted with alkali metal acetates such as potassium acetate, in a suitable solvent such as alcohols, lower alkanoic acids, or ketones (preferably in an alkanol such as ethanol) as described in the aforementioned application Serial No. 417,489.

By this reaction, compounds D are formed having a 9,8, 11,8-oxide radical, and a 21-substituent which is: hydrogen when the 2l-substituent of compounds C is hydrogen; acetoxy, when the 2l-substituent of compounds C is bromo; and chloro, when the 21-substituent of compounds C is chloro. In the case where the 21- substituent of compounds C is chloro, by reacting compounds C in the presence of an alkali metal iodide (e. g. potassium iodide) as well as the alkali metal acetate (e. g. potassium acetate), the 21-substituent in compounds D obtained is an acetoxy rather than a chloro radical.

Compounds D are then reacted with hydrogen halide (i. e. hydrofluoric, hydrochloric, hydrobromic, or hydroiodic acid) in a suitable solven (e. g. chloroform) as disclosed in the aforementioned application Serial No. 417,489. By this reaction, compounds E are formed having a 9ot-halo and llfi-hydroxy radical and a 21-substituent corresponding to the substituent in compounds D. The process of this invention is described in detail in the following schematic analysis and examples employing compound epi-F as a starting material, but is of course not limited thereto:

RIIIIXI CHsCO OK M-pregnene-l] (1,1 701,21 -tri0l-3,20-di0ne 1 1 0:,21 dimesylate (I) (epi-F 110c,21 -dimesylate) To a solution of 10 g. epi-F in 110 ml. anhydrous pyridine is added at 0 C. (all temperatures given hereinafter being in centrigrade) a solution of 6.6 ml. methanesulfonyl chloride in 10 ml. chloroform. The reaction mixture is allowed to remain at 0 for fifteen hours, after which 1 g. of ice is added. After an additional one-half hour at 0, the mixture is concentrated in vacuo to a small volume. The resulting residue is taken up in chloroform and water, and the chloroform solution is washed with cold dilute hydrochloric acid, dilute sodium bicarbonate solution, and finally with water. The chloroform solution is then dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue (about 12.4 g.) is recrystallized from 95% ethanol, yielding the analytically pure dimesylate, having the following properties: M. P. about 162 (dec.); [a] +97 (c, 0.98 in dioxane); analysis [calculated for C H O S (502.62): C, 53.26, H, 6.60; S, 12.36; found (approximately): C, 53.42; H, 6.29; S, 11.00].

EXAMPLE 2 21-chlor0-A -pregnene-1 1 rx-ol-3,20-di0ne 11 a-mesy late and epicorticosterone dimesylate To a solution of 164 mg. of epicorticosterone in 2 ml. of dry pyridine is added at 0 C. a solution of 11 ml. of methanesulfonyl chloride in 1 ml. of chloroform and the mixture is allowed to stand in the refrigerator overnight.

The excess mesyl chloride is destroyed with ice and the mixture worked up as described in Example 1. About 176 mg. of crystalline material is obtained, which after two recrystallizations from acetone-ether gives about 63 mg. of 21-chloro-A -pregnane-11u-ol-3,20-dione 11amesylate, M. P. 156-157 C. (dec.), [orb t-137 (c, 0.34 in chloroform;

32,? 238 In (E=16,65()), A 5.81 1, 6.04 t, 6.23 [L Analysis.Calcd. for C H O SCl (442.99): C, 59.65; H, 7.05; S, 7.24; Cl, 8.00. Found: C, 59.19; H, 6.91; S, 8.52; Cl, 7.78.

The material recovered from the mother liquor constitutes the Hall-dimesylate of epicorticosterone.

The following three examples illustrate the preparation of A -pregnene derivatives of this invention.

EXAMPLE 3 21 -br0m0-A (11 pregmzdiene-I 7a-0l-3,20-di0ne (II) A solution of mg. of epi-F dimesylate (I) (prepared as in Example 1), 25 mg. of anhydrous potassium acetate and 200 mg. of anhydrous lithium bromide in 6 ml. of glacial acetic acid is refluxed with the exclusion of moisture for 1 hour. The slightly colored solution is then evaporated to dryness in vacuo. The residue is taken up in chloroform and Water and washed with NaHCO and again with water. The dried chloroform solution is evap- 5 orated leaving a crystalline residue which weighs about 76 mg. Recrystallization from acetone givesprisms M. P. 198-199 (dec.), about 48 mg; M. P. 191-192 (dec.), about 13 mg, [al l06 (c, 0.56 in chloroform) yield: about 75%. rage 239 my (e=16 400), 280 m (e=995) M13929? 5.8 ,7, 6.12 t H Analysis.-Calcd. for C21H27O3BI' (407.35): C, 61.91; H, 6.68; Br, 19.62. Found: C, 61.79; H, 6.73; Br, 19.59.

EXAMPLE 4 A -pregnadiene-1 7a,2 1-di0l-3,20-di0ne 21 -acetate 21 -Chll0-A -pregnadiene-1 7a-0l-3,20-di0ne (III) A solution of 100 mg. of epi-F dimesylate (I), 25 mg. of anhydrous potassium acetate and 200 mg. of lithium chloride in 6 ml. of glacial acetic acid is refluxed for 1 hour with the exclusion of moisture. The acetic acid is removed in vacuo, the residue taken up in chloroform and water and the chloroform solution washed with bicarbonate solution and again with water. The chloroform solution is dried over sodium sulfate and on evaporation leaves about 68 mg. of a crystalline residue. Recrystallization from acetone yields about 49 mg.- (68%) M. P. 242-243 (dec.), [u] -|-120 (c, 0.36 in chloroform),

Nuiol x me 238 m 6:18.500), x m... 2 u, u. 610 I Analysis.-Calcd. for C H O Cl (362.89): C, 69.50; H, 7.50; CI, 9.77. Found: C, 69.94; H, 7.72; Cl, 9.75.

EXAMPLE 6 11 -pregnadiene-17a-0l-3,20-di0ne (IV) A solution of 100 mg. of epi-Fdimesylate (I), mg. of anhydrous potassium acetate and 400 mg. of sodium iodide in 6 ml. of glacial acetic acid is refluxed for minutes. The solution soon assumes the brown iodine color. At the end of the reaction time the acetic acid is removed in vacuo, the residue taken up in water and chloroform and the chloroform solution washed with sodium sulfite solution and water. After drying over sodium sulfate and evaporation of the solvent in vacuo, about 63 mg. of crystals (93%) are obtained. Recrystallization from acetone yields about43 .mg. of pure A -pregnadiene-17a-ol-3,20-dione, M. P. 2'16217, [0:15-1-63" (c, 0.39 in chloroform). Infrared-comparison shows identity with an authentic sample.

Following the procedure of Example 6 with the 21- chloro-1la-hydroxyprogesterone 1 la-mesylate of Example 2 substituted for epi-F dimesylate, 2-l-chloro-A pregnadiene-3,20-dione is produced.

The following examples illustrate the preparation of the 9u-halo,11,8-hydroxy pregnane derivatives in accordance with this invention:

EXAMPLE 7 901,21-dibr0mo-A -pregnene-1 7a,1119-di0l-3,20-di0ne (V) [9u,21-dibr0mo-115,17a-dihydroxyprogesterone] To a solution of 250 mg. of 2l-bromo-A -pregnadiene-17a-ol-3,20-dione (II) (M. P. 192-193) in 25 ml. of pure dioxane and 2.5 ml. water is added 125 mg. of N-bromacetamide and 1.5 ml. of 1 N H010 The mixture is stirred at room temperature and after 1 hour and 30 minutes the excess N-bromoacetamide is destroyed with Na SO solution. The reaction mixture is diluted with an equal volume of chloroform, the resulting aqueous layer separated off and the chloroform-dioxane layer washed with bicarbonate and water. After drying and evaporation of the solvents .in vacuo an oil is obtained which crystallized on addition of ether. The crystals are leached with more ether, and dried, M. P. 148-150 (dec.), about 237 mg. (77%). A sample is recrystallized twice from acetone-ether, M. P. 169-'-170 (dec.), [0415-1-161" (c, 0.39 in EtOH),

my} 242 my (e=17,400), 3.01 5.79 ,u, 6.10

Analysis.-Calcd. for C H O Br (504.27): C, 50.02; H, 5.60; Br, 31.70. Found: C, 50.68; H, 5.88; Br, 30.09.

EXAMPLE 8 To a solution of 100 mg. of 2l-chloro-A -preg nadiene-17a-ol-3,20-dione (III) in 10 ml. of dioxane and 1 ml. ofwater is added 56 mg. of N-bromoacetamide and 0.65 ml. of l N HClO The solution was stirred for 1% hours and the excess N-bromoacetamide is destroyed by the addition of a dilute sodium sulfite solution. After the .addition of 30 m1. of chloroform the resulting layers are separated and the chloroform-dioxane phase washed with water, NaHCO and again with Water, dried over sodium sulfate and evaporated in vacuo. An oil is obtained which crystallized on addition of acetoneether. About 78 mg. of crystals of M. P. 212-215" (dec.) are obtained. The mother liquors contain an additional 47 mg. The analytical sample is recrystallized from acetone-ether, M. P. 2 18219 (dec.), lal +l (c, 0.36 in chloroform) Analysis.-Calcd. for C H O BrCl (459.81): C,

54.85; H, 6.14; Br, 17.38. Found: C, 54.83; H, 6.02; Br, 18.34. IfExample 7 is repeated with dichloroclimethylhydantoin substituted *for N-bromoacetamide, 9u-chloro,21- bromo A pregnene-l l,B,17a-diol-3,20-dione (VII) chloro,21-bromo-11,8,17a-dihydroxyprogesterone] is produced.

If Example 8 is repeated with dichlorodimethylhydantoin substituted for N-bromoacetamide, 9a,21dichloro A pregnene 115,170 diol 3,20 dione (VIII) [9a,21-dichloro-l1B,17u-dihydroXyprogest-eronel is produced.

Nujol X max.

max.

EXAMPLE 9 9u-br0m0-A -pregnene-11 ,8,1 7a-diol-3,20-di0ne (IX) 330 mg. of A -pregnadiene-17u-ol-3,20-dione (IV) is treated with 200 mg. N-bromoacetamide, and the reaction mixture worked up as described in Example 7. The resulting crude product (about 450 mg.) is recrystallized from acetone-chloroform, and yields about 362 mg. (85%) pure 9a-bromo-l1B,17a-dihydroxyprogesterone, having the following properties: M. P. about 189- 191 (dec.); [a] +128 (c, 0.33 in chloroform) M13; 243 m (e=l6,700); N322 288 p (OH) 5.86 ,u. (ZO-ketone), 6.04 ,u,-6.08 ,u (A -3-ketone); analysis [calculated for C H O Br (425.36): C, 59.29; H, 6.87; Br, 18.79; found (approximately): C, 59.59; H, 6.81; Br, 18.61].

EXAMPLE 10 9a chloro A pregnene 115,170: diol 3,20 dione (X) [9a-chl0r0-11/3J7a-dihydroxy-progesterone] 110 mg. of A -pregnadiene-17a-ol-3,20-dione (IV) is dissolved in 20 ml. of dioxane and 2 ml. of water is added. To the resulting solution is added mg. of

N,N-dich1orodimethylhydantoin and 1 m1. of 1 N perchloric acid and the mixture is allowed to stand at room temperature for 30 minutes. Dilute aqueous sodium sulfite solution is added to destroy residual N,N-dichlorodimethylhydantoin and the mixture is diluted with 25 ml. of chloroform. which causes separation 'into two layers. The chloroform-dioxane phase is separated off, washed with water, sodium bicarbonate and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue (about 128 mg.) on recrystallization from acetone-chloroform-hexane yields pure 9a-chloro-1l5,17u-dihydroxyprogesterone, M. P. about 242243 C. (dec.). The compound is identified by infrared spectrum and mixture melting point comparison with an authentic sample. Yield about 58 mg.

If 21chloro-11 -pregnadiene-3,20-dione is substituted for compound IV in Examples 9 and 10, 21-chloro- 9m bromo A pregnene 115 ol 3,20 dione [21- chloro 9oz bromo 115 hydroxyprogesterone] and 911,21 dichloro A pregnene 115 ol 3,20 dione [9a,21 dichloro 11 -hydroxyprogesterone] are formed respectively.

The following examples illustrate the preparation of 95,115-oxido pregnane derivatives in accordance with this invention.

EXAMPLE 11 9 ,1 15-oxid0-A -pregnene-17a,21-di0l-3,2 0-di0ne 21-acetate (XI) A solution of 10 mg. of 911,2l-dibromo-M-pregnene- 17a,ll5-diol-3,20-dione (V) and 500 mg. of anhydrous potassium acetate in 25 ml. of absolute alcohol is refluxed for 2 /2 hours. The ethanol is removed in vacuo and the resulting residue taken up in water and chloroform and the chloroform solution washed free of salts. After drying and evaporation of the chloroform about 155 mg. of crystalline material are obtained. Recrystallization from acetone-ether affords about 50 mg. of pure material M. P. 207209 and about 17 mg. of M. P. 195196 (47%), [a] (c, 0.41 in chloroform). Infrared comparison showed identity with authentic 95,115-oxido-A -pregnene-17a,21-diol-3,20-dione 21 acetate (cf. the aforementioned application Serial No. 417,409).

EXAMPLE 1 2 21 chloro 95,115 oxido A pregnane 17a ol- 3,20-dione (XII) The process of Example 11 is repeated with 9oz-bI'OII10- 2l-chloro-A -pregnene-l15,l7a-diol-3,20-dione (VI) substituted for 901,21 dibromo A pregnene-17a,1l5-diol- 3,20-dione (V). The solution of VI and potassium acetate in absolute alcohol is refluxed for 20 minutes rather than 2 /2 hours. Isolation and purification in accordance with the method of Example 11 yields 2l-chloro-95,1l5-

oxido-M-pregnenel7a-ol-3,20-dione.

EXAMPLE 13 ZI-chlore-95,115-0xido-A -pregnene-3,20-di0ne o 0 method of Example 11, 21-chloro-95,115-oxido-A -pregnene-3,20-dione is obtained. 95,115-oxido-A -pregnene-17a,21-ol-3,20-dione 21-acetate (XI) may be converted to 9a-halo-A -pregnenel15,17a,21-triol-3,20-dione (9a-halohydrocortisone) and its 21-acyl derivatives (e. g., 9a-halohydrocortisone acetate) as well as the corresponding 9u-halo-A -pregnene- 170:,21-(1101-3,11,20-11110116 (9a-halocortisone) and its 21- acyl derivatives (e. g., 9a-halocortisone 2l-acetate) by the method disclosed in the aforementioned application Serial Number 417,489.

21 chloro 95,115 oxido A pregnene 17a ol- 3,20-dione (XII) similarly may be converted to the corresponding 21 chloro 9u-halo-A -pregnene-l15,1701- diol-3,20-dione as well as 21-chloro-9a-halo-A pregnenel7a-ol-3,11,20-trione, which are new steroids having mineraloand glucocorticoid activity; and 2l-chloro-95,ll5- oxido-M-pregnene-El,20-dione may also be converted to the corresponding 21-chloro-9a-halo-A pregnene--01- 3,20-dione as well as 21 chloro 9a halo-A -pregnene- 3,11,20-trione, which are new steroids having mineralocorticoid activity.

The invention may be otherwise embodied within the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of:

R i RI wherein R is hydrogen, R is hydroxy and together R and R is selected from the group consisting of keto and ketal, and Z is a radical selected from the group consisting of hydrogen and hydroxy.

2. 21 chloro 95,115 oxido A pregnene 17aol-3,20-dione.

3. 21-chloro-A -pregnene-11a-ol-3,20-dione 11 alkanesulfonate.

4. The process for producing a 95,115-oxido-2lchloro steroid of the pregnane series, which comprises reacting a 2l-chloro,9a-halo,1lfi-hydroxy-steroid of the pregnane series, wherein the halo radical is selected from the group consisting of bromine and chlorine, with an alkali metal acetate, and recovering the 95,115-oxido- 21-chloro steroid formed.

5. 21 chloro 95,115 oxido A pregnene-3,20-

dione.

' No references cited.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,851,455

Josef Fried et al.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 50, for chlorosteroids read chloro-steroids; column 2, lines 12 to 21, right-hand portion of formula should read as shown below instead of as in the patent column 3, line 16, for former read formed; line 19, for N-chloracetamide, read N-chloroacetamide,; line 36, for llfi-oxide radical read -11B-oxido radical; line 47, for in a suitable solven read in a suitable solvent; lines 56 to 65, right hand portion of formula should read as shown below instead of as in the patent CHzOSOzCHa CHaSOzO- Q MeX max.

line 40, for 610 11.. read 6.10,u.; column 6, line 39, for 584 610a read 5.84 6.10n.; line 64, for

column 7, line 31, for of 10 mg. of read --of 180 mg. of; column 8, line 3, for 93,11,8-oxido-A*-pregnene-l7a,2l-ol-3,20dione read 9,8,11/3-oX1do-A -pregnene-17a, 21-diol-3,20-dione; column 8, lines 27 to 47, claim 1, insert the word and between the two formulae.

Signed and sealed this 18th day of November 1958.

column 5, line 6, for

[SEAL] Attest: KARL H. AXLINE,

ROBERT C. WATSON,

ofice n September 9, 1958 V 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF:
 4. THE PROCESS FOR PRODUCING A 9B,11B-OXIDO-21CHLORO STERIOD OF THE PREGNANE SERIES, WHICH COMPRISES REACTING A 21-CHLORO,9A-HALO,11B-HYDROXY-STERIOD OF THE PREGNANE SERIES, WHEREIN THE HALO RADICAL IS SELECTED FROM THE GROUP CONSISTING OF BROMINE AND CHLORINE, WITH AN ALKALI METAL ACETATE, AND RECOVERING THE 9B,11B-OXIDO21-CHLORO STEROID FORMED. 